3-179234230-A-G

Variant names:

• chr3-179234230-A-G
• rs397517202
• NM_006218.4:c.3073A>G

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP2 PP5_Very_Strong

The NM_006218.4(PIK3CA):​c.3073A>G​(p.Thr1025Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1025S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PIK3CA NM_006218.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.85
• Publications: 111 publications found

Genes affected

PIK3CA (HGNC:8975): (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. This gene has been found to be oncogenic and has been implicated in cervical cancers. A pseudogene of this gene has been defined on chromosome 22. [provided by RefSeq, Apr 2016]

PIK3CA Gene-Disease associations (from GenCC):

• overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• megalencephaly-capillary malformation-polymicrogyria syndrome

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• vascular malformation

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cowden syndrome 5

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_006218.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-179234231-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 495324.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the PIK3CA gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 98 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 5.5986 (above the threshold of 3.09). Trascript score misZ: 6.1406 (above the threshold of 3.09). GenCC associations: The gene is linked to megalencephaly-capillary malformation-polymicrogyria syndrome, vascular malformation, Cowden syndrome 5, overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes, Cowden disease, hereditary breast carcinoma, familial ovarian cancer.
• PP5: Variant 3-179234230-A-G is Pathogenic according to our data. Variant chr3-179234230-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 45467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006218.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	NM_006218.4	MANE Select	c.3073A>G	p.Thr1025Ala	missense	Exon 21 of 21	NP_006209.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIK3CA	ENST00000263967.4	TSL:2 MANE Select	c.3073A>G	p.Thr1025Ala	missense	Exon 21 of 21	ENSP00000263967.3
	PIK3CA	ENST00000462255.2	TSL:3	n.2096A>G		non_coding_transcript_exon	Exon 11 of 11
	PIK3CA	ENST00000674534.1		n.3981A>G		non_coding_transcript_exon	Exon 15 of 15

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Mar 03, 2022

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in multiple cancer types and once in the literature in an individual with megalencephaly-capillary malformation (PMID: 22729224, PMID: 23982433). The p.Thr1025Ala variant substitute a threonine with an alanine in the kinase domain of the PIK3CA protein. Variants in this domain are typically activating (PMID: 18268322). This variant has also been observed in patient databases among individuals with cancer or PROS disorder, consisting of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi.

Sep 22, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23592320, 26453385, 16764926, 22997091, 19903786, 23982433, 34519764, 34858176, 35127508, 31217897, 22729224)

PIK3CA related overgrowth syndrome Pathogenic:1

Sep 07, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PIK3CA c.3073A>G (p.Thr1025Ala) was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals with capillary malformations (Rivière JB et al., PMID: 22729224; Mirzaa GM et al., PMID: 23592320; Mirzaa G et al., PMID: 27631024). This variant has been reported in the ClinVar database as a somatic pathogenic variant by multiple submitters and a germline likely pathogenic variant by one submitter (ClinVar ID: 45467). Additionally, it has been reported as a somatic variant in multiple cases in the cancer database cBioPortal. This variant is absent from the general population (gnomAD v3.1.2), indicating it is not a common variant. Another variant in the same codon, c.3074C>G (p.Thr1025Ser), has been reported in multiple cancer cases (Dhami J et al., PMID: 29588307; Gymnopoulos M et al., PMID: 17376864; ClinVar ID: 495324). The PIK3CA c.3073A>G (p.Thr1025Ala) variant resides within a catalytic domain, PI3Kc_IA_alpha, amino acids 695-1064, of PIK3CA that is defined as a critical functional domain (Zhao L et al., PMID: 18268322; Samuels Y et al., PMID: 15016963; Lai et al., PMID: 35997716). However, functional studies that correlate with the impact of this variant on PIK3CA function is lacking. The PIK3CA gene is defined by ClinGen's Brain Malformation expert panel as a gene with a low rate of benign missense variation and where pathogenic missense variants are a common disease mechanism (Lai et al, PMID: 35997716). A large number of PI3K/AKT pathway inhibitors are currently under clinical study in both PROS disorders and cancer (Jin N et al., PMID: 34779417; Venot Q et al., PMID: 29899452; Parker VER et al., PMID: 30270358). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the PIK3CA c.3073A>G (p.Thr1025Ala) variant is classified as likely pathogenic.

Non-small cell lung carcinoma Pathogenic:1

Aug 10, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Thr1025Ala variant has been reported in the literature as a somatic change in several different tumor types (endometrium, thyroid, large intestine, pituitary, lung carcinoma; COSMIC). Somatic PIK3CA variants have been identified in up to 4% of cases of lung cancer (Samuels 2004).

CLOVES syndrome Pathogenic:1

Jun 06, 2021

Medical Genetics Laboratory, Aldo Moro University of Bari

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.88	L
PhyloP100		8.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.59
Sift	Benign	0.12	T
Sift4G	Benign	0.12	T
Polyphen		0.85	P
Vest4		0.66
MutPred		0.51		Loss of phosphorylation at T1025 (P = 0.039)
MVP		0.95
MPC		2.6
ClinPred		0.90	D
GERP RS		6.1
Varity_R		0.63
gMVP		0.71
Mutation Taster		=4/96	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397517202; hg19: chr3-178952018; COSMIC: COSV55873252; COSMIC: COSV55873252;